DESCRIPTION (provided by 8applicant): The specific aims of this program are to develop a practical, flexible strategy for the enantioselective synthesis of six to nine membered ring ethers and apply the new strategies to the total synthesis of structurally novel and biologically important natural products. During the course of this investigation, new synthetic technologies will be explored for the asymmetric construction of medium ring ethers via olefin metathesis and tandem ring closing olefin metathesis reactions. Convenient access to alpha, alpha'-disubstituted ether linkages with control of the absolute stereochemistry at the positions alpha to the ether linkage is critical to the overall success of this program. Two important new approaches have already evolved from this program: 1) a syn or anti selective aldol reaction of chlorotitanium enolates of glycolyl oxazolidinethiones and 2) a highly versatile asymmetric glycolate alkylation reaction for the construction of alpha, alpha'-disubstituted ethers. Completion of the syntheses of brevetoxin A, gigantecin and mucocin are anticipated during the next grant period. Further development of the general approach to medium ring ethers will focus on the development of an intramolecular Diels-Alder approach to the eunicellin and cladiellin class of diterpenes including the cytotoxic agents astrogorgin and 4-Deoxyasbestinin A. A new strategy for the rapid construction of cis-2,6-distubstituted tetrahydropyrans that establishes both the C2 and the C6 stereogenic centers in a single step will also be investigated and applied to the total synthesis of the cytotoxin lasonolide A.